U.S. patent application number 10/571443 was filed with the patent office on 2006-12-28 for matrix metalloproteinase inhibitors.
Invention is credited to Simon Gaines, Ian Peter Holmes, Stephen Lewis Martin, Stephen Paul Watson.
Application Number | 20060293353 10/571443 |
Document ID | / |
Family ID | 29227079 |
Filed Date | 2006-12-28 |
United States Patent
Application |
20060293353 |
Kind Code |
A1 |
Gaines; Simon ; et
al. |
December 28, 2006 |
Matrix metalloproteinase inhibitors
Abstract
Compounds of Formula (I): ##STR1## wherein: A represents bond,
C.sub.1-6alkyl or CH.dbd.CH--C.sub.1-4alkyl; B represents bond, 0,
S, SO, SO.sub.2, CO, CR.sup.7R.sup.8, CO.sub.2R.sup.14,
CONR.sup.14R.sup.15, N(COR.sup.14)(COR.sup.15),
N(SO.sub.2R.sup.14)(COR.sup.15) or NR.sup.14R.sup.15; D represents
bond, or C.sub.1-6alkyl; E represents substituted aryl or
substituted or unsubstituted heteroaryl; Q represents an optionally
substituted 5- or 6-membered aryl or heteroaryl ring; X represents
O, S, SO, SO.sub.2, CO, CNR.sup.5, CNOR.sup.5, CNNR.sup.5R.sup.6,
NR.sup.11 or CR.sup.7R.sup.8; Y represents CR.sup.5OR.sup.11,
CR.sup.5SR.sup.11, NOR.sup.5, CR.sup.5NR.sup.6R.sup.11, SO,
SO.sub.2, CO, CNR.sup.5, CNOR.sup.5 or CS; R.sup.1 and R.sup.1'
each independently represents H, C.sub.1-6alkyl or
C.sub.1-4alkylaryl; R.sup.2 represents CO.sub.2R.sup.12,
CH.sub.2OR.sup.12 or CONR.sup.12R.sup.13, CONR.sup.12OR.sup.13,
NR.sup.12COR.sup.13, SR.sup.12, PO(OH).sub.2, PONHR.sup.12 or
SONHR.sup.12; R.sup.3 represents H, C.sub.1-6alkyl or
C.sub.1-4alkylaryl; R.sup.4 represents optionally substituted aryl
or heteroaryl; Z represents a bond, CH.sub.2, O, S, SO, SO.sub.2,
NR.sup.5, OCR.sup.5R.sup.6, CR.sup.9R.sup.10O or Z, R.sup.4 and Q
together form an optionally substituted fused tricyclic group;
R.sup.5 and R.sup.6 each independently represent H, C.sub.1-6 alkyl
or C.sub.1-4 alkylaryl; R.sup.7 and R.sup.8 each independently
represent H, halo, C.sub.1-6 alkyl or C.sub.1-4 alkylaryl; R.sup.9
and R.sup.10 each independently represents H, C.sub.1-6 alkyl
optionally substituted by halo, cyano, OR.sup.11 or
NR.sup.6R.sup.11, C.sub.1-4 alkylaryl optionally substituted by
halo, cyano, OR11 or NR.sup.6R.sup.11, OR.sup.11 or, together with
the N to which they are attached, R.sup.9 and R.sup.10 form a
heterocyclic group: R.sup.11 represents H, C.sub.1-6 alkyl,
C.sub.1-4 alkylaryl or COR.sup.5; R.sup.12 and R.sup.13 each
independently represent H, C.sub.1-3 alkyl, C.sub.1-3 alkylaryl or
C.sub.1-3 alkylheteroaryl or, together with the functionality to
which they are attached, R.sup.12 and R.sup.13 form a heterocyclic
group: R.sup.14 and R.sup.15 each independently represent H,
C.sub.1-6 alkyl, C.sub.1-4 alkylaryl or C.sub.1-4 alkylheteroaryl
or together with the functionality to which they are attached
R.sup.14 and R.sup.15 form a heterocyclic or fused heterocyclic
group; and physiologically functional derivatives thereof,
corresponding processes for preparation, pharmaceutical
formulations containing them and their use as inhibitors of matrix
metallproteinase enzymes (MMPs).
Inventors: |
Gaines; Simon;
(Hertfordshire, GB) ; Holmes; Ian Peter;
(Hertfordshire, GB) ; Martin; Stephen Lewis;
(Hertfordshire, GB) ; Watson; Stephen Paul;
(Hertfordshire, GB) |
Correspondence
Address: |
SMITHKLINE BEECHAM CORPORATION;CORPORATE INTELLECTUAL PROPERTY-US, UW2220
P. O. BOX 1539
KING OF PRUSSIA
PA
19406-0939
US
|
Family ID: |
29227079 |
Appl. No.: |
10/571443 |
Filed: |
September 10, 2004 |
PCT Filed: |
September 10, 2004 |
PCT NO: |
PCT/EP04/10319 |
371 Date: |
March 13, 2006 |
Current U.S.
Class: |
514/269 ;
514/416; 544/296; 544/310; 548/453; 548/472 |
Current CPC
Class: |
A61P 43/00 20180101;
A61P 37/00 20180101; A61P 37/06 20180101; C07D 239/54 20130101;
C07D 209/48 20130101; A61P 29/00 20180101; A61P 37/02 20180101;
C07D 405/10 20130101; C07D 403/10 20130101 |
Class at
Publication: |
514/269 ;
514/416; 544/296; 544/310; 548/453; 548/472 |
International
Class: |
A61K 31/513 20060101
A61K031/513; A61K 31/4035 20060101 A61K031/4035; C07D 409/02
20060101 C07D409/02; C07D 403/02 20060101 C07D403/02 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 13, 2003 |
GB |
0321538.1 |
Claims
1. A compound of formula (I): ##STR49## wherein: A represents bond,
C.sub.1-6alkyl or CH.dbd.CH--C.sub.1-4alkyl; B represents bond, O,
S, SO, SO.sub.2, CO, CR.sup.7R.sup.8, CO.sub.2R.sup.14,
CONR.sup.14R.sup.15, N(COR.sup.14)(COR.sup.15),
N(SO.sub.2R.sup.14)(COR.sup.15), NR.sup.14R.sup.15; D represents
bond, or C.sub.1-6alkyl; E represents substituted aryl or
substituted or unsubstituted heteroaryl; Q represents an optionally
substituted 5- or 6-membered aryl or heteroaryl ring; X represents
O, S, SO, SO.sub.2, CO, CNR.sup.5, CNOR.sup.5, CNNR.sup.5R.sup.6,
NR.sup.11 or CR.sup.7R.sup.8; Y represents CR.sup.5OR.sup.11,
CR.sup.5SR.sup.11, NOR.sup.5, CR.sup.5NR.sup.6R.sup.11, SO,
SO.sub.2, CO, CNR5, CNOR.sup.5 or CS; R.sup.1 and R.sup.1' each
independently represents H, C.sub.1-6alkyl or C.sub.1-4alkylaryl;
R.sup.2 represents CO.sub.2R.sup.12, CH.sub.2OR.sup.12 or
CONR.sup.12R.sup.13, CONR.sup.12OR.sup.13, NR.sup.12COR.sup.13,
SR.sup.12, PO(OH).sub.2, PONHR.sup.12 or SONHR.sup.12; R.sup.3
represents H, C.sub.1-6alkyl or C.sub.1-4alkylaryl; R.sup.4
represents optionally substituted aryl or heteroaryl; Z represents
a bond, CH.sub.2, O, S, SO, SO2, NR.sup.5, OCR.sup.5R.sup.6,
CR.sup.9R.sup.10O or Z, R.sup.4 and Q together form an optionally
substituted fused tricyclic group; R.sup.5 and R.sup.6 each
independently represent H, C.sub.1-6 alkyl or C.sub.1-4 alkylaryl;
R.sup.7 and R.sup.8 each independently represent H, halo, C.sub.1-6
alkyl or C.sub.1-4 alkylaryl; R.sup.9 and R.sup.10 each
independently represents H, C.sub.1-6 alkyl optionally substituted
by halo, cyano, OR.sup.11 or NR.sup.6R.sup.11, C.sub.1-4 alkylaryl
optionally substituted by halo, cyano, OR.sup.11 or
NR.sup.6R.sup.11, OR.sup.11 or, together with the N to which they
are attached, R.sup.9 and R.sup.10 form a heterocyclic group
optionally containing one or more further heteroatoms selected from
O, N and S; R.sup.11 represents H, C.sub.1-6 alkyl, C.sub.1-4
alkylaryl or COR.sup.5; R.sup.12 and R.sup.13 each independently
represent H, C.sub.1-3 alkyl, C.sub.1-3 alkylaryl or C.sub.1-3
alkylheteroaryl or, together with the functionality to which they
are attached, R.sup.12 and R.sup.13 form a heterocyclic group
optionally containing one or more further atoms selected from C, O,
N and S; R.sup.14 and R.sup.15 each independently represent H,
C.sub.1-6 alkyl, C.sub.1-4 alkylaryl or C.sub.1-4 alkylheteroaryl
or together with the functionality to which they are attached
R.sup.14 and R.sup.15 form a heterocyclic or fused heterocyclic
group which may contain one or more further atoms selected from C,
O, N and S; and physiologically functional derivatives thereof.
2. A compound as claimed in claim 1 of formula (Ia) or (Ib):
##STR50## wherein: T is absent or represents O, S, NR.sup.16 or
CR.sup.16R.sup.17; --- represents optional bonds; G.sup.1 and
G.sup.2 each independently represents CH or N; A represents bond,
C.sub.1-6alkyl or CH.dbd.CH--C.sub.1-4alkyl; B represents bond, O,
S, SO, SO.sub.2, CO, CR.sup.7R.sup.8, CO.sub.2R.sup.14,
CONR.sup.14R.sup.15, N(COR.sup.14)(COR.sup.15),
N(SO.sub.2R.sup.14)(COR.sup.15), NR.sup.14R.sup.15; D represents
bond, or C.sub.1-6 alkyl; E represents substituted aryl or
substituted or unsubstituted heteroaryl; R.sup.16 represents H,
C.sub.1-6 alkyl or C.sub.1-4 alkylaryl; R.sup.17 represents H or
C.sub.1-6 alkyl; R.sup.18 and R.sup.19 each independently
represents halo, cyano, nitro, OR.sup.16, SR.sup.16, COR.sup.16,
NR.sup.17COR.sup.16, CONR.sup.16R.sup.17, optionally substituted
phenoxy or C.sub.1-6alkyl optionally substituted by OR.sup.16; m
and n each independently represents 0 or an integer 1, 2 or 3; and
physiologically functional derivatives thereof.
3. A compound as claimed in claim 1 of formula (Ic): ##STR51## A
represents bond, C.sub.1-6alkyl or CH.dbd.CH--C.sub.1-4alkyl; B
represents bond, O, S, SO, SO.sub.2, CO, CR.sup.7R.sup.8,
CO.sub.2R.sup.14, CONR.sup.14R.sup.15, N(COR.sup.14)(COR.sup.15),
N(SO.sub.2R.sup.14)(COR.sup.15), NR.sup.14R.sup.15 D represents
bond, or C.sub.1-6 alkyl; E represents substituted aryl or
substituted or unsubstituted heteroaryl; R.sup.18 and R.sup.19 each
independently represents halo, cyano, nitro, OR.sup.16, SR.sup.16,
COR.sup.16, NR.sup.17COR.sup.16, CONR.sup.16R.sup.17, optionally
substituted phenoxy or C.sub.1-6alkyl optionally substituted by
OR.sup.16; m and n each independently represents 0 or an integer 1,
2 or 3; and physiologically functional derivatives thereof.
4. A compound as claimed in claim 1 of formula (Id): ##STR52##
wherein R.sup.20 represents a substituted or unsubstituted aryl or
heteroaryl group selected from phenyl, benzofuraryl and
pyrimidinyl; and ##STR53## represents a substituted aryl or a
substituted or unsubstituted heteroaryl group comprising at least
one nitrogen atom; and physiologically functional derivatives
thereof.
5. A compound as claimed in claim 1 selected from:
5-Biphenyl-4-yl-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hyd-
roxypentanoic acid;
5-Biphenyl-4-yl-3-hydroxy-2-[2-(3-methyl-2,6-dioxo-3,6-dihydropyrimidin-1
(2H)-yl)ethyl]pentanoic acid;
5-Biphenyl-4-yl-3-hydroxy-2-[2-(3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1
(2H)-yl)ethyl]pentanoic acid;
5-(4'-Acetylbiphenyl-4-yl)-3-hydroxy-2-[2-(3-methyl-2,4-dioxo-3,4-dihydro-
pyrimidin-1(2H)-yl)ethyl]pentanoic acid;
3-Hydroxy-2-[2-(3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1
(2H)-yl)ethyl]-5-(4-pyrimidin-5-ylphenyl)pentanoic acid;
3-Hydroxy-2-[2-(3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1
(2H)-yl)ethyl]-5-[4'-(trifluoromethoxy)biphenyl-4-yl]pentanoic
acid;
5-[4-(1-Benzofuran-2-yl)phenyl]-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-
-yl)ethyl]-3-hydroxypentanoic acid;
2-[2-(1,3-Doxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-[4'-(trifl-
uoromethoxy)biphenyl-4-yl]pentanoic acid;
2-[2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-[4'-(meth-
ylthio)biphenyl-4-yl]pentanoic acid;
5-(4'-Cyanobiphenyl-4-yl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)et-
hyl]-3-hydroxypentanoic acid;
5-(4'-Acetylbiphenyl-4-yl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)e-
thyl]-3-hydroxypentanoic acid; and
2-[2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-(4-pyrimi-
din-5-ylphenyl)pentanoic acid.
6. A compound as claimed in claim 1 for use in medicine.
7. A method for treatment of a human or animal subject suffering
from or susceptible to an autoimmune disorder or an inflammatory
condition which method comprises administering to said human or
animal subject an effective amount of a compound as claimed in
claim 1.
8. (canceled)
9. A pharmaceutical composition comprising a compound as claimed in
claim 1 and a pharmaceutically acceptable carrier therefore, and
optionally one or more other therapeutic agents.
10. A process for preparation of compounds of formula (I) as
defined in claim 1, which process comprises: (A) for the
preparation of a compound of formula (I) wherein Z represents a
bond, reacting a compound of formula (II): ##STR54## wherein
R.sup.1, R.sup.1', R.sup.2, R.sup.3, R.sup.3', A, B, D, E, Q, X and
Y are as previously defined for formula (I) and L represents a
leaving group, with a reagent suitable to introduce the group
R.sup.4; (B) for the preparation of a compound of formula (I)
wherein Z represents O, S, SO, SO.sub.2, or NR.sup.5, reacting a
compound of formula (III): ##STR55## wherein Q, X, Y, R.sup.1,
R.sup.1', R.sup.2, R.sup.3, A, B, D and E are as previously defined
for formula (I), and T represents OH, SH or NR.sup.6H, with a
reagent suitable to introduce the group R.sup.4, followed in the
case where T is SH by optional oxidation of the sulfide to the
sulfoxide or the sulfone; (C) for the preparation of a compound of
formula (I) wherein Z represents OCR.sup.4R.sup.5, reacting a
compound of formula (IV): ##STR56## wherein Q, X, Y, R.sup.1,
R.sup.1', R.sup.2, R.sup.3, R.sup.5, R.sup.6, A, B, D and E are as
previously defined for formula (I), with a reagent suitable to
introduce the group R.sup.4-O; (D) for the preparation of a
compound of formula (I) wherein Z represents CR.sup.5R.sup.6O,
reacting a compound of formula (V): ##STR57## wherein Q, X, Y,
R.sup.1, R.sup.1', R.sup.2, R.sup.3, A, B, D and E are as
previously defined for formula (I), with a reagent suitable to
introduce the group R.sup.4CR.sup.5R.sup.6; (E) for the preparation
of a compound of formula (I) wherein Z represents CH.sub.2,
reacting a compound of formula (I) comprises reacting a compound of
formula (VI): ##STR58## wherein Q, X, Y, R.sup.1, R.sup.1',
R.sup.2, R.sup.3, A, B, D and E are as previously defined for
formula (I), with a reagent suitable to introduce the group
R.sup.4CH.sub.2; (F) for the preparation of a compound of formula
(I) reacting a compound of formula (VII): ##STR59## wherein Q, X,
Y, R.sup.1, R.sup.1', R.sup.2, R.sup.3, R.sup.4, A, B and D are as
previously defined for formula (I), with a reagent suitable to
introduce the group E; or (G) carrying out a process selected from
processes (A) to (F) followed by interconversion of one or more
functional groups.
Description
[0001] This invention relates to novel chemical compounds,
processes for their preparation, pharmaceutical formulations
containing them and their use in therapy.
[0002] The compounds of the invention are inhibitors of matrix
metalloproteinase enzymes (MMPs).
[0003] Matrix metalloproteinase enzymes play a major role in
extracellular matrix component degradation and remodelling.
Examples of MMPs include collagenase 1, 2 and 3, gelatinase A and
B, stromelysin 1,2 and 3, matrilysin, macrophage metalloelastase,
enamelysin and membrane type 1,2,3 and 4 MMP. The enzymes are
secreted by connective tissue cells and inflammatory cells. Enzyme
activation can not only initiate tissue damage but induce increased
inflammatory cell infiltration into the tissue, leading to more
enzyme production and subsequent tissue damage. For example,
elastin fragments produced by MMP degradation are believed to
stimulate inflammation by attracting macrophages to the site of MMP
activity. Inhibition of MMPs provides a means for treating disease
states wherein inappropriate metalloprotease activity results in
degradation of connective tissue and inflammation.
[0004] In one aspect, the present invention provides compounds of
formula (I): ##STR2## Wherein: A represents bond, C.sub.1-6alkyl or
CH.dbd.CH--C.sub.1-4alkyl; B represents bond, O, S, SO, SO.sub.2,
CO, CR.sup.7R.sup.8, CO.sub.2R.sup.14, CONR.sup.14R.sup.15,
N(COR.sup.14)(COR.sup.15), N(SO.sub.2R.sup.14)(COR.sup.15) or
NR.sup.14R.sup.15; D represents bond, or C.sub.1-6alkyl; E
represents substituted aryl or substituted or unsubstituted
heteroaryl; Q represents an optionally substituted 5- or 6-membered
aryl or heteroaryl ring; X represents O, S, SO, SO.sub.2, CO,
CNR.sup.5, CNOR.sup.5, CNNR.sup.5R.sup.6, NR.sup.11 or
CR.sup.7R.sup.8; Y represents CR.sup.5OR.sup.11, CR.sup.5SR.sup.11,
NOR.sup.5, CR.sup.5NR.sup.6R.sup.11, SO, SO.sub.2, CO, CNR.sup.5,
CNOR.sup.5 or CS; R.sup.1 and R.sup.1' each independently
represents H, C.sub.1-6alkyl or C.sub.1-4alkylaryl; R.sup.2
represents CO.sub.2R.sup.12, CH.sub.2OR.sup.12 or
CONR.sup.12R.sup.13, CONR.sup.12OR.sup.13, NR.sup.12COR.sup.13,
SR.sup.12, PO(OH).sub.2, PONHR.sup.12 or SONHR.sup.12; R.sup.3
represents H, C.sub.1-6alkyl or C.sub.1-4alkylaryl; R.sup.4
represents optionally substituted aryl or heteroaryl; Z represents
a bond, CH.sub.2, O, S, SO, SO.sub.2, NR.sup.5, OCR.sup.5R.sup.6,
CR.sup.9R.sup.10O or Z, R.sup.4 and Q together form an optionally
substituted fused tricyclic group; R.sup.5 and R.sup.6 each
independently represent H, C.sub.1-6 alkyl or C.sub.1-4 alkylaryl;
R.sup.7 and R.sup.8 each independently represent H, halo, C.sub.1-6
alkyl or C.sub.1-4 alkylaryl; R.sup.9 and R.sup.10 each
independently represents H, C.sub.1-6 alkyl optionally substituted
by halo, cyano, OR.sup.11 or NR.sup.6R.sup.11, C.sub.1-4 alkylaryl
optionally substituted by halo, cyano, OR11 or NR.sup.6R.sup.11,
OR.sup.11 or, together with the N to which they are attached,
R.sup.9 and R.sup.10 form a heterocyclic group optionally
containing one or more further heteroatoms selected from O, N and
S; R.sup.11 represents H, C.sub.1-6 alkyl, C.sub.1-4 alkylaryl or
COR.sup.5; R.sup.12 and R.sup.13 each independently represent H,
C.sub.1-3alkyl, C.sub.1-3 alkylaryl or C.sub.1-3 alkylheteroaryl
or, together with the functionality to which they are attached,
R.sup.12 and R.sup.13 form a heterocyclic group optionally
containing one or more further atoms selected from C, O, N and S;
R.sup.14 and R.sup.15 each independently represent H, C.sub.1-6
alkyl, C.sub.1-4 alkylaryl or C.sub.1-4 alkylheteroaryl or together
with the functionality to which they are attached R.sup.14 and
R.sup.15 form a heterocyclic or fused heterocyclic group which may
contain one or more further atoms selected from C, O, N and S; and
physiologically functional derivatives thereof.
[0005] References to `aryl` include references to monocyclic
carbocyclic aromatic rings (e.g. phenyl) and bicyclic carbocyclic
aromatic rings (e.g. naphthyl) and references to `heteroaryl`
include references to mono- and bicyclic heterocyclic aromatic
rings containing 1-3 hetero atoms selected from nitrogen, oxygen
and sulphur. In a bicyclic heterocyclic aromatic group there may be
one or more hetero-atoms in each of the rings, or only in one ring.
Examples of monocyclic heterocyclic aromatic rings include
pyridinyl, pyrimidinyl, thiophenyl, furanyl, pyrrolyl, oxazolyl,
isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, uracil or
imidazolyl, and examples of bicyclic heterocyclic aromatic rings
include benzofuranyl, benzimidazolyl, quinolinyl or indolyl.
Carbocyclic and heterocyclic aromatic rings may be optionally
substituted, e.g. by one or more C.sub.1-6 alkyl, C.sub.2-6
alkenyl, halogen, C.sub.1-6 alkoxy, cyano, hydroxy, nitro, amino,
--N(CH.sub.3).sub.2, --NHCOC.sub.1-6 alkyl, --OCF.sub.3,
--CF.sub.3, --COOC.sub.1-6 alkyl, --OCHCF.sub.2, --SCF.sub.3,
--CONR6R7 --SO.sub.2N(CH.sub.3).sub.2, --SO.sub.2CH.sub.3 or
--SCH.sub.3 groups, or by fused cycloalkyl or heterocyclic rings
which may themselves be substituted, for example by carbonyl
groups.
[0006] References to `alkyl` include references to both straight
chain and branched chain aliphatic isomers of the corresponding
alkyl. It will be appreciated that references to alkylene and
alkoxy shall be interpreted similarly.
[0007] Suitably A represents bond or C.sub.1-6 alkyl, such as
C.sub.2 or C.sub.3 alkyl.
[0008] Suitably B represents bond.
[0009] Suitably D represents methylene or bond, preferably
bond.
[0010] For Example A-B-D may suitably represent
--CH.sub.2CH.sub.2--.
[0011] Optional substituents for E include one or more of C.sub.1-6
alkyl, C.sub.2-6 alkenyl, halogen, C.sub.1-6 alkoxy, cyano,
hydroxy, nitro, amino, --N(CH.sub.3).sub.2, --NHCOC.sub.1-6 alkyl,
--OCF.sub.3, --CF.sub.3, --COOC.sub.1-6 alkyl, --OCHCF.sub.2,
--SCF.sub.3, --CONR.sup.5R.sup.6 --SO.sub.2N(CH.sub.3).sub.2,
--SO.sub.2CH.sub.3 or --SCH.sub.3 groups, or by fused cycloalkyl or
heterocyclic rings which may themselves be substituted, for example
by carbonyl groups.
[0012] In one subgroup of compounds according to the invention, E
represents substituted or unsubstituted 5- or 6- membered
heteroaryl such as a nitrogen-containing heteroaromatic group, for
example, uracil.
[0013] In a further subgroup of compounds according to the
invention, E represents aryl, such as phenyl, substituted by a
fused substituted or unsubstituted heterocyclic ring, such as a
nitrogen-containing heterocyclic ring. Exemplary of this subgroup
are compounds according to the invention wherein E represents
phthalimido.
[0014] Suitable optional substituents for Q include one or more of
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, halogen, C.sub.1-6 alkoxy,
cyano, hydroxy, nitro, amino, --N(CH.sub.3).sub.2, --NHCOC.sub.1-6
alkyl, --OCF.sub.3, --CF.sub.3, --COOC.sub.1-6 alkyl,
--OCHCF.sub.2, --SCF.sub.3,
--CONR.sup.5R.sup.6--SO.sub.2N(CH.sub.3).sub.2, --SO.sub.2CH.sub.3
or --SCH.sub.3 groups. Most suitably Q represents unsubstituted
phenyl.
[0015] Suitably, R.sup.1 and R.sup.1' each represents hydrogen.
[0016] Suitably R.sup.2 represents CO.sub.2R.sup.12, such as
CO.sub.2H.
[0017] Suitably R.sup.3 represents hydrogen.
[0018] Suitably R.sup.4 benzofuranyl, phenyl or pyrimidinyl.
Suitable optional substituents for R.sup.4 include one or more of
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, halogen, C.sub.1-6 alkoxy,
cyano, hydroxy, nitro, amino, --N(CH.sub.3).sub.2, --NHCOC.sub.1-6
alkyl, --OCF.sub.3, --CF.sub.3, --COOC.sub.1-6 alkyl,
--OCHCF.sub.2, --SCF.sub.3, --CONR.sup.5R.sup.6,
--SO.sub.2N(CH.sub.3).sub.2, --SO.sub.2CH.sub.3 or --SCH.sub.3
groups. Preferably R.sup.4 represents optionally substituted phenyl
or optionally substituted pyrimidinyl.
[0019] Suitably X represents CH.sub.2.
[0020] Suitably Y represents CHOR.sup.11, where R.sup.11 suitably
represents H, C.sub.1-6 alkyl or COR.sup.5. Preferably R.sup.11
represents H. R.sup.5 preferably represents C.sub.1-6 alkyl.
[0021] Suitably Z represents a bond, or Z, R4 and Q together
represent a fused tricyclic group. Preferably, Z represents a
bond.
[0022] A subgroup of compounds of formula (I) is presented by
formula (Ia) and formula (Ib): ##STR3## wherein: T is absent or
represents O, S, NR.sup.16 or CR.sup.16R.sup.17; --- represents
optional bonds; G.sup.1 and G.sup.2 each independently represents
CH or N; A represents bond, C.sub.1-6alkyl or
CH.dbd.CH--C.sub.1-4alkyl; B represents bond, O, S, SO, SO.sub.2,
CO, CR.sup.7R.sup.8, CO.sub.2R.sup.14, CNR.sup.14R.sup.15,
N(COR.sup.14)(COR.sup.15), N(SO.sub.2R.sup.14)(COR.sup.15),
NR.sup.14R.sup.15; D represents bond, or C.sub.1-6 alkyl; E
represents substituted aryl or substituted or unsubstituted
heteroaryl; R.sup.16 represents H, C.sub.1-6alkyl or C.sub.1-4
alkylaryl; R.sup.17 represents H or C.sub.1-4alkyl; R.sup.18 and
R.sup.19 each independently represents halo, cyano, nitro,
OR.sup.16, SR.sup.16, COR.sup.16, NR.sup.17COR.sup.16,
CONR.sup.16R.sup.17, optionally substituted phenoxy or
C.sub.1-6alkyl optionally substituted by OR.sup.16; m and n each
independently represents 0 or an integer 1, 2 or 3; and
physiologically functional derivatives thereof.
[0023] In compounds of formulae (Ia) and (Ib), A suitably
represents alkyl, such as C.sub.1-4alkyl, for example ethyl.
Suitably, B represents bond. Suitably D represents bond. Suitably E
represents substituted or unsubstituted heteroaryl such as
nitrogen-containing heteroaryl, for example uracil, or E represents
phenyl substituted by a fused substituted or unsubstituted
heterocyclic ring, such as phthalimido.
[0024] Preferably n is 0 and m is 1.
[0025] Preferably R.sup.18 represents a para-substituent selected
from NO.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halo, SC.sub.1-6
alkyl, CN and COC.sub.1-6 alkyl.
[0026] Preferably, G.sup.1 and G.sup.2 are both CH or both N.
[0027] A further subgroup of compounds according to the invention
is represented by compounds of formula (Ic): ##STR4## wherein
A,B,D,E,R.sup.18 and m are as defined for formulae (Ia) and (Ib)
above; and physiologically functional derivatives thereof.
[0028] In compounds of formula (Ic), A-B-D suitably represents
--CH.sub.2--CH.sub.2--. Suitably m represents 0 or 1. When m is 1,
R.sup.18 suitably represents a para substituent selected from
NO.sub.2, C.sub.1-6 alkyl, C.sub.1-6alkoxy, halo, SC.sub.1-6alkyl,
CN, OCF.sub.3, or COC.sub.1-6 alkyl.
[0029] A further subgroup of compounds according to the intention
is represented by compounds of formula (Id): ##STR5## wherein
R.sup.20 represents a substituted or unsubstituted aryl or
heteroaryl group selected from phenyl, benzofuraryl and
pyrimidinyl; and ##STR6## represents a substituted aryl or a
substituted or unsubstituted heteroaryl group comprising at least
one nitrogen atom; and physiologically functional derivatives
thereof.
[0030] In compounds of formula (Id), R.sup.20 suitably represents
unsubstituted or substituted phenyl, unsubstituted benzofuraryl or
unsubstituted pyrimidinyl. When R.sup.20 represents substituted
phenyl, suitably the phenyl ring will be substituted by a single
substituent in the para position. Suitable substituents include
C.sub.1-6alkyl, C.sub.2-6alkenyl, halogen, C.sub.1-6alkoxy, cyano,
hydroxy, nitro, amino, --N(CH.sub.3).sub.2, --NHCOC.sub.1-6alkyl,
--OCF.sub.3, --CF.sub.3, --CO.sub.2C.sub.1-6alkyl, OCHCF.sub.2,
--SCF.sub.3, --CONR.sup.5R.sup.6, --SO.sub.2N(CH.sub.3).sub.2,
--SO.sub.2CH.sub.3 or --SCH.sub.3, such as cyano, COCH.sub.3,
OCF.sub.3 and SCH.sub.3.
[0031] By the term "physiologically functional derivative" is meant
a chemical derivative of a compound of formula (I) having the same
physiological function as the free compound of formula (I), for
example, by being convertible in the body thereto and includes any
pharmaceutically acceptable esters, amides and carbamates, salts
and solvates of compounds of formula (I) which, upon administration
to the recipient, are capable of providing (directly or indirectly)
compounds of formula (I) or active metabolite or residue
thereof.
[0032] Suitable salts of the compounds of formula (I) include
physiologically acceptable salts and salts which may not be
physiologically acceptable but may be useful in the preparation of
compounds of formula (I) and physiologically acceptable salts
thereof. If appropriate, acid addition salts may be derived from
inorganic or organic acids, for example hydrochlorides,
hydrobromides, sulphates, phosphates, acetates, benzoates,
citrates, succinates, lactates, tartrates, fumarates, maleates,
1-hydroxy-2-naphthoates, palmoates, methanesulphonates, formates or
trifluoroacetates.
[0033] Examples of solvates include hydrates.
[0034] When compounds of formula (I) contain chiral centres, the
invention extends to mixtures of enantiomers (including racemic
mixtures) and diastereoisomers as well as to individual
enantiomers. Generally it is preferred to use a compound of formula
(I) in the form of a purified single enantiomer. Enantiomerically
pure compounds of formula (I) are available by way of chirally
selective synthesis or by way of chiral separation.
[0035] The compounds of formula (I) and salts and solvates thereof
may be prepared by the methodology described hereinafter,
constituting a further aspect of this invention.
[0036] A first process (A) according to the invention for preparing
a compound of formula (I) wherein Z represents a bond comprises
reacting a compound of formula (II): ##STR7## wherein R.sup.1,
R.sup.1', R.sup.2, R.sup.3, R.sup.3', A, B, D, E, Q, X and Y are as
previously defined for formula (I) and L represents a leaving
group, with a reagent suitable to introduce the group R.sup.4, such
as a compound R.sup.4B(OH).sub.2, suitably in the presence of a
catalyst, such as a noble metal catalyst e.g. palladium, and a
suitable base, such as an alkali metal carbonate, e.g. caesium
carbonate. The reaction is conveniently carried out in a suitable
solvent, such as a polar organic solvent, e.g. dimethyl formamide.
Suitable leaving groups represented by L include halides,
especially bromide or iodide.
[0037] For example, for the synthesis of a (optionally substituted)
biphenyl compound according to the invention (ie Q and R.sup.4 are
both phenyl), a phenyl boronic acid may be reacted with
[(4-bromophenyl)(methylsulfonyl)amino]acetic acid in the presence
of a suitable catalyst: ##STR8##
[0038] A second process (B) according to the invention for
preparing a compound of formula (I) wherein Z represents O, S, SO,
SO.sub.2, or NR.sup.5, comprises reacting a compound of formula
(III): ##STR9## wherein Q, X, Y, R.sup.1, R.sup.1', R.sup.2,
R.sup.3, A, B, D and E are as previously defined for formula (I),
and T represents OH, SH or NR.sup.6H, with a reagent suitable to
introduce the group R.sup.4, such as a compound R.sup.4-L, wherein
L is a suitable leaving group. The reaction is conveniently carried
out in a suitable solvent, such as a solvent containing a
heteroatom, e.g. pyridine in the presence of a suitable catalyst,
for example a palladium catalyst (preferred for T=NR.sup.5H) or a
copper catalyst (preferred for T=OH or SH). Suitable leaving groups
represented by L include halides, especially bromide or iodide.
[0039] For compounds in which Z represents SO or SO.sub.2, the
compound of formula (I) may conveniently be prepared by initial
preparation of the compound in which Z represents S, followed by
oxidation of the sulphide to the sulfoxide or the sulfone. The
oxidation step may be carried out using methods known in the art
such as oxidation with hydrogen peroxide in the case of the
sulfone, or oxidation with Oxone.RTM. (potassium peroxymonosulfate)
in the case of the sulfoxide.
[0040] A third process (C) according to the invention for preparing
a compound of formula (I) wherein Z represents OCR.sup.5R.sup.6,
comprises reacting a compound of formula (IV): ##STR10## wherein Q,
X, Y, R.sup.1, R.sup.1', R.sup.2, R.sup.3, R.sup.5, R.sup.6, A, B,
D and E are as previously defined for formula (I), with a reagent
suitable to introduce the group R.sup.4-O such as a compound
R.sup.4-OH. The reaction is conveniently carried out in a suitable
solvent, such as an alcohol solvent, e.g. ethanol, under basic
conditions, for example in the presence of an aqueous hydroxide
such as sodium hydroxide. Suitable leaving groups represented by L
include halides, especially bromide or iodide.
[0041] A fourth process (D) according to the invention for
preparing a compound of formula (I) wherein Z represents
CR.sup.5R.sup.6O, comprises reacting a compound of formula (V):
##STR11## wherein Q, X, Y, R.sup.1, R.sup.1', R.sup.2, R.sup.3, A,
B, D and E are as previously defined for formula (I), with a
reagent suitable to introduce the group R.sup.4CR.sup.5R.sup.6 such
as a compound R.sup.4CR.sup.5R.sup.6-L, wherein L is a suitable
leaving group. The reaction is conveniently carried out in a
suitable solvent, such as an alcohol solvent, e.g. ethanol, under
basic conditions, for example in the presence of an aqueous
hydroxide such as sodium hydroxide. Suitable leaving groups
represented by L include halides, especially bromide or iodide.
[0042] A fifth process (E) according to the invention for preparing
a compound of formula (I) wherein Z represents CH.sub.2, comprises
reacting a compound of formula (VI): ##STR12## wherein Q, X, Y,
R.sup.1, R.sup.1', R.sup.2, R.sup.3, A, B, D and E are as
previously defined for formula (I), with a reagent suitable to
introduce the group R.sup.4CH.sub.2, such as a compound
R.sup.4CH.sub.2-L, wherein L is a suitable leaving group, for
example halide, suitably in the presence of a catalyst, for example
a Lewis acid catalyst such as AlCl.sub.3. A Friedel-Crafts reaction
may accordingly be appropriate.
[0043] A sixth process (F) according to the invention for preparing
a compound of formula (I) comprises reacting a compound of formula
(VII) ##STR13## wherein Q, X, Y, R.sup.1, R.sup.1', R.sup.2,
R.sup.3, R.sup.4, A, B and D are as previously defined for formula
(I), with a reagent suitable to introduce the group E such as a
compound H-E. The reaction is conveniently carried out in a
suitable solvent, such as an aprotic solvent, e.g.
dimethylformamide, under basic conditions, for example in the
presence of a base such as potassium hydride. Suitable leaving
groups represented by L include halides, such as bromide or iodide,
and methylsulphonyloxy groups.
[0044] A seventh process (G) according to the invention comprises
carrying out a process selected from processes (A) to (F) followed
by interconversion of one or more functional groups.
Interconversion processes include processes such as oxidation,
reduction, substitution, deprotection etc., standard in the art of
synthetic chemistry.
[0045] Compounds of formula (II), (III), (IV), (V) and (VI) may be
prepared by reaction of compounds of formula (VIII): ##STR14##
wherein Q, X, Y, R.sup.1, R.sup.1', R.sup.2, R.sup.3, A, B and D
are as previously defined for formula (I) and U is L in the case of
compound (II), T in the case of compound (III),
L(R.sup.5)(R.sup.6)CH.sub.2 in the case of compound (IV), OH in the
case of compound (V) and H in the case of compound (VI), and
L.sup.2 represents a leaving group more labile than L, with a
compound of formula E-H or a salt of formula E.sup.-M.sup.+.
Suitable leaving groups represented by L.sup.2 include halides,
such as bromide or iodide, and methylsulphonyloxy groups.
Alternatively, an activated leaving group L.sup.2 of the Mitsunobu
type may be generated by reacting a corresponding alcohol with
diisopropylazodicarboxylate and triphenylphosphine; that leaving
group may then be displaced by an anion E.sup.-M.sup.+ to generate
the product.
[0046] Compounds of formula (VIII) may in turn be prepared by
reaction of compounds of formula (IX): ##STR15## wherein Q, X, Y,
R.sup.1, R.sup.1', R.sup.2 and R.sup.3 are as previously defined
for formula (I), U is as previously defined for formula (VIII) and
L.sup.3 represents a leaving group, with a compound of formula
H-A-B-D-L.sup.2. The reaction is conveniently carried out in a
suitable solvent, such as an aprotic solvent, e.g.
dimethylformamide in the presence of a suitable catalyst, for
example a metal hydride.
[0047] Compounds of formula (IX) may in turn be prepared by
reaction of compounds of formula (X) with compounds of formula
(XI): ##STR16## wherein Q, X, Y, R.sup.1 , R.sup.1', R.sup.2 and
R.sup.3 are as previously defined for formula (I), U is as
previously defined for formula (VII), L.sup.3 is as previously
defined for formula (IX), and L.sup.4 represents a leaving group.
The reaction is conveniently carried out in a suitable solvent,
such as an aprotic solvent, e.g. tetrahydrofuran in the presence of
a suitable catalyst, for example a metal hydride.
[0048] Analogously, compounds of formula (VII) may be prepared by
reaction of compounds of formula (XII): ##STR17## wherein Q, X, Y,
R.sup.1, R.sup.1', R.sup.2, R.sup.3 and R.sup.4 are as previously
defined for formula (VII), and L.sup.3 represents a leaving group,
with a compound of formula H-A-B-D-L. The reaction is conveniently
carried out in a suitable solvent, such as an aprotic solvent, e.g.
dimethylformamide in the presence of a suitable catalyst, for
example a metal hydride.
[0049] Compounds of formula (XII) may in turn be prepared by
reaction of compounds of formula (XIII) with compounds of formula
(XIV): ##STR18## wherein Q, X, Y, R.sup.1, R.sup.1', R.sup.2,
R.sup.3 and R.sup.4 are as previously defined for formula (I)
L.sup.3 is as previously defined for formula (XII), and L.sup.4
represents a leaving group. The reaction is conveniently carried
out in a suitable solvent, such as an aprotic solvent, e.g.
tetrahydrofuran in the presence of a suitable catalyst, for example
a metal hydride.
[0050] Compounds of formula R.sup.4B(OH).sub.2, R.sup.4-L,
R.sup.4-OH, R.sup.4CR.sup.5R.sup.6-L, R.sup.4CH.sub.2-L, H-E,
H-A-B-D-L.sup.2, (X), (XI), (XIII) and (XIV) are known or may be
prepared from known compounds by methods familiar to those skilled
in the art.
[0051] Depending on the identity of the group X, group Y, group
R.sup.2, L, L.sup.2, L.sup.3 and L.sup.4 it may be preferable for
one or more of those groups to be protected during one or more
steps of the synthesis of a compound of formula (I). Suitable
protecting groups are known to those skilled in the art. Protecting
groups may be any conventional protecting groups, for example as
described in "Protective Groups in Organic Synthesis" by Theodora
Greene and Peter G. M. Wuts (John Wiley and Sons Inc. 1999).
[0052] Enantiomeric compounds of the invention may be obtained (a)
by the separation of the components of the corresponding racemic
mixture, for example, by chiral chromatography, enzymatic
resolution methods or preparing and separating suitable
diastereoisomers, (b) by direct synthesis from the appropriate
chiral starting materials by the methods described above, or (c) by
methods analogous to those described above using chiral
reagents.
[0053] Optional conversion of a compound of formula (I) to a
corresponding salt may conveniently be effected by reaction with
the appropriate acid or base. Optional conversion of a compound of
formula (I) to a corresponding solvate or other physiologically
functional derivative may be effected by methods known to those
skilled in the art.
[0054] Compounds of formula (I) may be useful for the treatment of
any conditions in which inhibition of matrix metalloproteinase
would be beneficial, especially in the treatment of inflammatory
diseases and autoimmune disorders.
[0055] Examples of inflammatory conditions and autoimmune disorders
in which the compounds of the invention have potentially beneficial
effects include diseases of the respiratory tract such as asthma
(including allergen-induced asthmatic reactions), cystic fibrosis,
bronchitis (including chronic bronchitis), chronic obstructive
pulmonary disease (COPD), adult respiratory distress syndrome
(ARDS), chronic pulmonary inflammation, rhinitis and upper
respiratory tract inflammatory disorders (URID), ventilator induced
lung injury, silicosis, pulmonary sarcoidosis, idiopathic pulmonary
fibrosis, bronchopulmonary dysplasia, arthritis, e.g. rheumatoid
arthritis, osteoarthritis, infectious arthritis, psoriatic
arthritis, traumatic arthritis, rubella arthritis, Reiter's
syndrome, gouty arthritis and prosthetic joint failure, gout, acute
synovitis, spondylitis and non-articular inflammatory conditions,
e.g. herniated/ruptured/prolapsed intervertebral disk syndrome,
bursitis, tendonitis, tenosynovitic, fibromyalgic syndrome and
other inflammatory conditions associated with ligamentous sprain
and regional musculoskeletal strain, inflammatory disorders of the
gastrointestinal tract, e.g. ulcerative colitis, diverticulitis,
Crohn's disease, inflammatory bowel diseases, irritable bowel
syndrome and gastritis, multiple sclerosis, systemic lupus
erythematosus, scleroderma, autoimmune exocrinopathy, autoimmune
encephalomyelitis, diabetes, tumor angiogenesis and metastasis,
cancer including carcinoma of the breast, colon, rectum, lung,
kidney, ovary, stomach, uterus, pancreas, liver, oral, laryngeal
and prostate, melanoma, acute and chronic leukemia, periodontal
disease, neurodegenerative disease, Alzheimer's disease,
Parkinson's disease, epilepsy, muscle degeneration, inguinal
hernia, retinal degeneration, diabetic retinopathy, macular
degeneration, ocular inflammation, bone resorption diseases,
osteoporosis, osteopetrosis, graft vs. host reaction, allograft
rejections, sepsis, endotoxemia, toxic shock syndrome,
tuberculosis, usual interstitial and cryptogenic organizing
pneumonia, bacterial meningitis, systemic cachexia, cachexia
secondary to infection or malignancy, cachexia secondary to
acquired immune deficiency syndrome (AIDS), malaria, leprosy,
leishmaniasis, Lyme disease, glomerulonephritis,
glomerulosclerosis, renal fibrosis, liver fibrosis, pancreatitis,
hepatitis, endometriosis, pain, e.g. that associated with
inflammation and/or trauma, inflammatory diseases of the skin, e.g.
dermatitis, dermatosis, skin ulcers, psoriasis, eczema, systemic
vasculitis, vascular dementia, thrombosis, atherosclerosis,
restenosis, reperfusion injury, plaque calcification, myocarditis,
aneurysm, stroke, pulmonary hypertension, left ventricular
remodeling and heart failure.
[0056] Diseases of principal interest include COPD and inflammatory
diseases of the respiratory tract and joints and vascular
diseases.
[0057] It will be appreciated by those skilled in the art that
reference herein to treatment extends to prophylaxis as well as the
treatment of established conditions.
[0058] There is thus provided as a further aspect of the invention
a compound of formula (I) or a physiologically acceptable
derivative thereof for use in medicine.
[0059] According to another aspect of the invention, there is
provided the use of a compound of formula (I) or a physiologically
acceptable derivative thereof for the manufacture of a medicament
for the treatment of inflammatory conditions or autoimmune
disorders.
[0060] In a further or alternative aspect there is provided a
method for the treatment of a human or animal subject suffering
from or susceptible to an autoimmune disorder or an inflammatory
condition which method comprises administering to said human or
animal subject an effective amount of a compound of formula (I) or
a physiologically functional derivative thereof.
[0061] The compounds according to the invention may be formulated
for administration in any convenient way, and the invention
therefore also includes within its scope pharmaceutical
compositions comprising a compound of formula (I) or a
physiologically acceptable derivative thereof together, if
desirable, with one or more physiologically acceptable diluents or
carriers.
[0062] There is also provided a process for preparing such a
pharmaceutical formulation which comprises mixing the
ingredients.
[0063] The compounds according to the invention may, for example,
be formulated for oral, inhaled, intranasal, topical, buccal,
parenteral or rectal administration, preferably for oral
administration.
[0064] Tablets and capsules for oral administration may contain
conventional excipients such as binding agents, for example syrup,
acacia, gelatin, sorbitol, tragacanth, mucilage of starch,
cellulose or polyvinyl pyrrolidone; fillers, for example, lactose,
microcrystalline cellulose, sugar, maize- starch, calcium phosphate
or sorbitol; lubricants, for example, magnesium stearate, stearic
acid, talc, polyethylene glycol or silica; disintegrants, for
example, potato starch, croscarmellose sodium or sodium starch
glycollate; or wetting agents such as sodium lauryl sulphate. The
tablets may be coated according to methods well known in the art.
Oral liquid preparations may be in the form of, for example,
aqueous or oily suspensions, solutions, emulsions, syrups or
elixirs, or may be presented as a dry product for constitution with
water or other suitable vehicle before use. Such liquid
preparations may contain conventional additives such as suspending
agents, for example, sorbitol syrup, methyl cellulose,
glucose/sugar syrup, gelatin, hydroxymethyl cellulose,
carboxymethyl cellulose, aluminium stearate gel or hydrogenated
edible fats; emulsifying agents, for example, lecithin, sorbitan
mono-oleate or acacia; non-aqueous vehicles (which may include
edible oils), for example almond oil, fractionated coconut oil,
oily esters, propylene glycol or ethyl alcohol; or preservatives,
for example, methyl or propyl p-hydroxybenzoates or sorbic acid.
The preparations may also contain buffer salts, flavouring,
colouring and/or sweetening agents (e.g. mannitol) as
appropriate.
[0065] Compounds according to the invention for topical
administration may be formulated as creams, gels, ointments or
lotions or as a transdermal patch. Such compositions may for
example be formulated with an aqueous or oily base with the
addition of suitable thickening, gelling, emulsifying, stabilising,
dispersing, suspending, and/or colouring agents.
[0066] Lotions may be formulated with an aqueous or oily base and
will in general also contain one or more emulsifying agents,
stabilising agents, dispersing agents, suspending agents,
thickening agents, or colouring agents. They may also contain a
preservative.
[0067] For buccal administration the compositions may take the form
of tablets or lozenges formulated in conventional manner.
[0068] The compounds may also be formulated as suppositories, e.g.
containing conventional suppository bases such as cocoa butter or
other glycerides.
[0069] The compounds according to the invention may also be
formulated for parenteral administration by bolus injection or
continuous infusion and may be presented in unit dose form, for
instance as ampoules, vials, small volume infusions or pre-filled
syringes, or in multi-dose containers with an added preservative.
The compositions may take such forms as solutions, suspensions, or
emulsions in aqueous or non-aqueous vehicles, and may contain
formulatory agents such as anti-oxidants, buffers, antimicrobial
agents and/or tonicity adjusting agents. Alternatively, the active
ingredient may be in powder form for constitution with a suitable
vehicle, e.g. sterile, pyrogen-free water, before use. The dry
solid presentation may be prepared by filling a sterile powder
aseptically into individual sterile containers or by filling a
sterile solution aseptically into each container and
freeze-drying.
[0070] The pharmaceutical compositions according to the invention
may also be used in combination with other therapeutic agents, for
example anti-inflammatory agents (such as corticosteroids (e.g.
fluticasone propionate, beclomethasone dipropionate, mometasone
furoate, triamcinolone acetonide or budesonide) or NSAIDs (e.g.
sodium cromoglycate, nedocromil sodium, PDE4 inhibitors,
leukotriene antagonists, CCR-3 antagonists, iNOS inhibitors,
tryptase and elastase inhibitors, beta-2 integrin antagonists and
adenosine 2a agonists)) or beta adrenergic agents (such as
salmeterol, salbutamol, formoterol, fenoterol or terbutaline and
salts thereof) or antiinfective agents (e.g. antibiotics,
antivirals).
[0071] It will be appreciated that when the compounds of the
present invention are administered in combination with other
therapeutic agents normally administered by the inhaled or
intranasal route, that the resultant pharmaceutical composition may
be administered by the inhaled or intranasal route.
[0072] Compounds of the invention may conveniently be administered
in amounts of, for example, 0.01 to 100 mg/kg body weight,
preferably 0.1 to 25 mg/kg body weight, more preferably 0.3 to 5
mg/kg body weight,. The compounds may be given more than once daily
to be equivalent to the total daily dose. The precise dose will of
course depend on the age and condition of the patient and the
particular route of administration chosen and will ultimately be at
the discretion of the attendant physician.
[0073] No toxicological effects are expected when a compound
according to the present invention is administered in the above
mentioned dose range.
[0074] Compounds of the invention may be tested for in vitro
activity in accordance with the following assay:
[0075] The fluorescent peptide substrate used in the MMP-12 assay
is FAM-Gly-Pro-Leu-Gly-Leu-Phe-Ala-Arg-Lys(TAMRA), where FAM
represents carboxyfluorescein, and TAMRA represents
tetramethylrhodamine. MMP12 catalytic domain (residues 106-268)
protein was expressed in E. coli in the form of insoluble inclusion
bodies & stored in concentrated solution under denaturing
conditions (8M guanidine hydrochloride). Enzyme was refolded into
active form in situ by direct dilution into assay reactions. The 51
uL reactions are run in NUNC-brand black,square 384-well plates,
each well containing 2 uM substrate, 20 nM enzyme, and 0.001-100 uM
inhibitor, in 50 mM HEPES, pH 7.5, 150 mM NaCl, 10 mM CaCl2, 1 uM
ZnAc, 0.6 mM CHAPS, and 2% DMSO. Postitive control wells contain no
inhibitor. Negative control wells are effected by either
pre-dispensing the EDTA quench (see below) or by omiting enyme.
Reactions are incubated at ambient temperature for 120 min, then
quenched by the addition of 15uL of 100 mM EDTA. Product formation
in each well is quantified by measuring flourescense with a
Molecular Devices Acquest. The excitation wavelength is set at 485
nM, and the emmision wavelenght is 530 nM. IC.sub.50 values were
obtained by first calculating the percent inhibition (% I) at each
inhibitor concentration (% I=100*(1-(I-C2)/(C1-C2)), where C1 is
the mean of the positive controls, and C2 is the mean of the
negative controls), then fitting the % I vs. inhibitor
concentration [I] data to: % I=A+((B-A)/(1+((C/[I] D))), where A is
the lower asymptote, B is the upper asymptote, C is the IC50 value,
and D is the slope factor. When tested in this assay, compounds of
Examples 1 to 12 had IC50s below 100 micromolar.
[0076] The invention may be illustrated by reference to the
following examples, which should not be construed as a limitation
thereto:
General Experimental Details
LC/MS Data Were Obtained Under the Following Conditions:
[0077] Column: 3.3 cm.times.4.6 mm ID, 3 um ABZ+PLUS [0078] Flow
Rate: 3 ml/min [0079] Injection Volume: 5 .mu.l [0080] Temp: RT
[0081] UV Detection Range: 215 to 330 nm Solvents: A: 0.1% Formic
Acid+10 mMolar Ammonium Acetate. [0082] B: 95% Acetonitrile+0.05%
Formic Acid
[0083] Gradient: TABLE-US-00001 Time A % B % 0.00 100 0 0.70 100 0
4.20 0 100 5.30 0 100 5.50 100 0
[0084] .sup.1HNMR spectra were obtained at 400 MHz on a
Bruker-Spectrospin Ultrashield 400 spectrophotometer.
EXAMPLE 1
5-Biphenyl-4-yl-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydr-
oxypentanoic acid
[0085] ##STR19##
[0086] Potassium phthalimide (8.8 mg, 60 .mu.mol) was added in one
portion to a stirred solution of 1,1-dimethylethyl
5-(4-biphenylyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)-2-{2-[(methylsulfon-
yl) oxy]ethyl}pentanoate (28.4 mg, 50 .mu.mol) in dimethylformamide
(0.5 mL) under nitrogen at room temperature. The resulting solution
was heated at 80.degree. C. for 1 h 45 min then cooled to room
temperature. The volatiles were evaporated and the residue taken up
in dichloromethane (0.5 mL). Trifloroacetic acid (0.5 mL) was added
in one portion and the resulting solution stirred for 1 h at room
temperature. The volatiles were evaporated and the residue purified
by mass directed auto-preparative HPLC to give the title compound
as a white solid (6.0 mg, 27%). LC/MS: 3.43 min; z/e 444, calcd
(M+1) 444. .sup.1H NMR (400 MHz: CDCl.sub.3): 7.85 (2H), 7.70 (2H),
7.55 (1H), 7.50 (1H), 7.45 (2H), 7.30 (1H), 7.25 (4H), 3.85(3H),
2.95 (1H), 2.75 (1H), 2.60(1H), 2.20 (1H), 2.05 (1H), 1.90
(2H).
EXAMPLE 2
5-Biphenyl-4-yl-3-hydroxy-2-[2-(3-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(-
2H)-yl)ethyl]pentanoic acid
[0087] ##STR20##
[0088] Prepared by an analogous reaction sequence to example 1.
LC/MS: 2.96 min; z/e 423, calcd (M+1) 423.
EXAMPLE 3
5-Biphenyl-4-yl-3-hydroxy-2-[2-(3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1
(2H)-yl)ethyl]pentanoic acid
[0089] ##STR21##
[0090] Prepared by an analogous reaction sequence to example 1.
LC/MS: 2.98 min; z/e 423, calcd (M+1) 423.
EXAMPLE 4
5-(4'-Acetylbiphenyl-4-yl)-3-hydroxy-2-[2-(3-methyl-2,4-dioxo-3,4-dihydrop-
yrimidin-1(2H)-yl)ethyl]pentanoic acid
[0091] ##STR22##
[0092] A solution of
3-hydroxy-5-(4-iodophenyl)-2-[2-(3-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyr-
imidinyl)ethyl]pentanoic acid (10 mg, 21 .mu.mol) in
dimethylformamide (0.5 mL) was added in one portion to a mixture of
p-acetylbenzeneboronic acid (4.0 mg, 25 .mu.mol) and fibrecat
FC1001 (2.71% Pd; 8.3 mg, 2.0 .mu.mol) in a Smith microwave
reaction vial. Aqueous sodium carbonate solution (1.0 M; 53 .mu.L,
53 .mu.mol) was added and the vial capped. The crude reaction
mixture was heated at 150.degree. C. for 15 min using a Smith
Synthesiser microwave reactor. On cooling the vial was opened and
the contents filtered through a Whatman 5 .mu.M filter tube,
washing the filter cake with methanol (2.times.1 mL). The filtrate
was evaporated and the resulting residue was purified using mass
directed auto-preparative reverse phase HPLC to give the title
compound (6.0 mg, 61%) as a white solid. LC/MS: 2.82 min; z/e 465,
calcd (M+1) 465. H NMR (400 MHz: DMSO-d.sub.6): 8.00 (2H), 7.80
(2H), 7.60 (4H), 7.30 (2H), 6.65 (1H), 3.70 (3H), 3.10 (3H), 2.80
(1H), 2.60 (2H), 2.30 (1H), 1.85 (2H), 1.60 (1H).
EXAMPLE 5
3-Hydroxy-2-[2-(3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethyl]-5--
(4-pyrimidin-5-ylphenyl)pentanoic acid
[0093] ##STR23##
[0094] Prepared by an analogous reaction sequence to example 4.
LC/MS: 2.27 min; z/e 425, calcd (M+1) 425.
EXAMPLE 6
3-Hydroxy-2-[2-(3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethyl]-5--
[4'-(trifluoromethoxy)biphenyl-4-yl]pentanoic acid
[0095] ##STR24##
[0096] Prepared by an analogous reaction sequence to example 4.
LC/MS: 3.28 min; z/e 506, calcd (M+1) 506.
EXAMPLE 7
5-[4-(1-Benzofuran-2-yl)phenyl]-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2--
yl)ethyl]-3-hydroxypentanoic acid
[0097] ##STR25##
[0098] A solution of
2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-(4-iodoph-
enyl) pentanoic acid (25 mg, 50 .mu.mol) in dimethylformamide (1.0
mL) was added in one portion to a mixture of
-benzofuran-2-ylboronic acid (11 mg, 70 .mu.mol) and fibrecat
FC1001 (2.71% Pd; 20 mg, 5.0 .mu.mol) in a Smith microwave reaction
vial. Cesium carbonate (41.0 mg, 125 .mu.mol) was added and the
vial capped. The crude reaction mixture was heated at 150.degree.
C. for 15 min using a Smith Synthesiser microwave reactor. On
cooling the vial was opened and the contents partitioned between
methanol/dichloromethane (10:90; 10 mL) and aqueous hydrochloric
acid solution (2.0 M; 10 mL). The organic phase was separated and
filtered through a Whatman 5 .mu.M filter tube, washing the filter
cake with methanol (2.times.1 mL). The filtrate was evaporated and
the resulting residue was purified using mass directed
auto-preparative reverse phase HPLC to give the title compound (3.0
mg, 12%) as a pale yellow solid. LC/MS: 3.69 min; z/e 484, calcd
(M+1) 484. .sup.1H NMR (400 MHz: DMSO-d.sub.6): 7.80 (6H), 7.65
(2H), 7.30 (5H), 3.65 (1H), 3.60 (2H), 2.75 (1H), 2.55 (1H), 2.40
(1H major), 2.25 (1H minor), 1.85 (2H), 1.65 (2H).
EXAMPLE 8
2-[2-(1,3-Doxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-[4'-(triflu-
oromethoxy)biphenyl-4-yl]pentanoic acid
[0099] ##STR26##
[0100] Prepared by an analogous reaction sequence to example 7.
LC/MS: 3.72 min; z/e 528, calcd (M+1) 528.
EXAMPLE 9
2-[2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-[4'-(methy-
lthio)biphenyl-4-yl]pentanoic acid
[0101] ##STR27##
[0102] Prepared by an analogous reaction sequence to example 7.
LC/MS: 3.61 min; z/e 490, calcd (M+1) 490.
EXAMPLE 10
5-(4'-Cyanobiphenyl-4-yl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)eth-
yl]-3-hydroxypentanoic acid
[0103] ##STR28##
[0104] Prepared by an analogous reaction sequence to example 7.
LC/MS: 3.34 min; z/e 469, calcd (M+1) 469.
EXAMPLE 11
5-(4'-Acetylbiphenyl-4-yl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)et-
hyl]-3-hydroxypentanoic acid
[0105] ##STR29##
[0106] Prepared by an analogous reaction sequence to example 7.
LC/MS: 3.28 min; z/e 486, calcd (M+1) 486.
EXAMPLE 12
2-[2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-(4-pyrimid-
in-5-ylphenyl)pentanoic acid
[0107] ##STR30##
[0108] Prepared by an analogous reaction sequence to example 7.
LC/MS: 2.70 min; z/e 446, calcd (M+1) 446.
Intermediate 1: 4-Bromomethyl-biphenyl
[0109] ##STR31##
[0110] Carbon tetrabromide (8.99 g, 27.1 mmol) and triphenyl
phosphine (7.11 g, 27.1 mmol) were added to a stirred solution of
biphenyl-4-yl methanol (5.00 g, 27.1 mmol) in dichloromethane (100
mL) at room temperature. Stirring was continued at room temperature
for 1.5 hours then the solvent removed by evaporation under reduced
pressure. The residue was purified by column chromatography on
silica gel (1:20 diethyl ether: cyclohexane) to give the title
compound (6.37 g, 95%) as a white solid. .sup.1H NMR (400 MHz:
CDCl.sub.3): 7.6 (4H), 7.45 (4H), 7.35 (1H), 4.55 (2H).
Intermediate 2: 5-Biphenyl-4-yl-3-oxo-pentanoic acid tert-butyl
ester
[0111] ##STR32##
[0112] A solution of t-butyl acetoaceate (1.84 mL, 11.1 mmol) in
tetrahydrofuran (20 mL) was added to a stirred suspension of sodium
hydride (488 mg, 12.2 mmol) in tetrahydrofuran (10 mL) at 0.degree.
C. under nitrogen. After stirring for 10 minutes n-butyl lithium
(1.6 M in hexanes; 7.3 mL, 11.6 mmol) was added dropwise over 2
minutes then stirring was continued for a further 10 minutes. A
solution of 4-bromomethyl-biphenyl (Intermediate 1, 3.00 g, 12.2
mmol) in tetrahydrofuran (6 mL) was added dropwise over 10 minutes
and the resulting solution stirred at 0.degree. C. for 1.5 hours. 6
M Hydrochloric acid (15 mL) was added; then the crude reaction
mixture was extracted with diethyl ether (3.times.50 mL). The
organic phases were combined, washed with brine (50 mL), dried
(MgSO.sub.4) then the solvent evaporated under reduced pressure.
The residue was purified by column chromatography on silica gel
(1:20 diethyl ether: cyclohexane) to give the title compound (1.37
g, 38%) as a yellow solid. LC/MS: 3.78 min; z/e 342, calcd
(M+NH.sub.4) 342. .sup.1H NMR (400 MHz: CDCl.sub.3): 7.55 (2H),
7.50 (2H), 7.43 (2H), 7.32 (1H), 7.25 (2H), 3.34 (2H), 2.95 (4H),
1.45 (9H).
Intermediate 3: tert-Butyl
5-biphenyl-4-yl-2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-oxopentanoa-
te
[0113] ##STR33##
[0114] A solution of 5-biphenyl-4-yl-3-oxo-pentanoic acid
tert-butyl ester (13.7 g, 42.4 mmol) in dimethylformamide (10 mL)
was added dropwise over 20 min to a stirred suspension of sodium
hydride (60% mineral oil suspension; 1.78 g, 44.4 mmol) in
dimethylformamide (10 mL) at 0.degree. C. under nitrogen. After
stirring for 20 min (2-bromoethoxy)-t-butyldimethylsilane (10.0 g,
46.4 mmol) was added dropwise over 20 min at 0.degree. C. then the
reaction heated to 70.degree. C. for 2.5 h. On cooling to room
temperature the reaction was quenched by careful addition of water
(5 mL) then the volatiles evaporated. The residue was partitioned
between saturated aqueous ammonium chloride solution (200 mL) and
dichloromethane (200 mL) and the phases separated. The aqueous
phase was washed with dichloromethane (3.times.200 mL) then the
organic phases combined, washed with brine (200 mL), dried (sodium
sulfate) and the solvent evaporated. The residue was
chromatographed on silica gel (10% diethyl ether: cyclohexane) to
give the title compound (12.1 g, 59%) as colourless oil which was a
mixture of diastereomers. LC/MS: 4.70 min; z/e 483, calcd (M+1)
483. .sup.1H NMR (400 MHz: CDCl.sub.3): 7.55 (2H), 7.50 (2H), 7.40
(2H), 7.35 (1H), 7.25 (2H), 3.60 (2H), 2.95 (3H), 2.20 (1H minor)
2.0 (1H major), 1.55 (1H), 1.45 (11H), 0.85 (9H), 0.5 (6H).
Intermediate 4: tert-Butyl
5-biphenyl-4-yl-2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-hydroxypent-
anoate
[0115] ##STR34##
[0116] Sodium borohydride (1.05 g, 27.7 mmol) was added portion
wise to a stirred solution of tert-butyl
5-biphenyl-4-yl-2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-oxopentanoa-
te (12.1 g, 25.2 mmol) in methanol (80 mL) at 0.degree. C. under
nitrogen. On completion of addition stirring was continued for 1.5
h then the reaction was quenched with saturated aqueous ammonium
chloride solution (80 mL). The resulting mixture was extracted with
diethyl ether (3.times.200 mL) then the organic layers were
combined, washed with brine (100 mL), dried (magnesium sulfate) and
the solvent evaporated. The residue was chromatographed on silica
gel (10% to 50% diethyl ether: cyclohexane) to give the title
compound (8.47 g, 69%) as a colourless oil which was a mixture of
diastereomers. LC/MS: 4.49 min; z/e 485, calcd (M+1) 485. .sup.1H
NMR (400 MHz: CDCl.sub.3): 7.60 (2H), 7.50 (2H), 7.45 (2H), 3.90
(1H minor), 3.80 (1H minor), 3.70 (1H major), 3.65 (1H major), 3.25
(1H minor), 3.00 (1H major), 2.90 (1H), 2.75 (1H), 2.60 (1H major),
2.55 (1H minor), 1.90 (1H), 1.85 (2H), 1.45 (10H), 0.90 (9H), 0.5
(6H).
Intermediate 5: 4-Methoxybenzyl 2,2,2-trichloroethanimidoate
[0117] ##STR35##
[0118] 4-Methoxybenzyl 2,2,2-trichloroethanimidoate was prepared
using the procedure of Smith, Amos B. Iii; Qiu, Yuping; Kaufman,
Michael; Arimoto, Hirokazu; Jones, David R.; Kobayashi, Kaoru;
Beauchamp, Thomas J. "Preparation of intermediates for the
synthesis of discodermolides and their polyhydroxy dienyl lactone
derivatives for pharmaceutical use"- WO 0004865.
Intermediate 6: 1,1-Dimethylethyl
5-(4-biphenylyl)-2-(2-{[(1,1-dimethylethyl)
(dimethyl)silyl]oxy}ethyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)pentanoate
[0119] ##STR36##
[0120] Boron trifluoride etherate (8.0 .mu.L, 65 .mu.mol) was added
to a stirred solution of tert-butyl
5-biphenyl-4-yl-2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-hydroxypent-
anoate (7.88 g, 16.3 mmol) and 4-methoxybenzyl
2,2,2-trichloroethanimidoate (6.88 g, 24.5 mmol) in tetrahydrofuran
(40 mL) at 0.degree. C. under nitrogen. The reaction was allowed to
warm to room temperature at which stirring was continued for 2 h. A
further portion of boron trifluoride etherate (8.0 .mu.L, 65
.mu.mol) was then added and stirring was continued at room
temperature for a further 2 h. Two further additions of boron
trifluoride etherate (8.0 .mu.L, 65 .mu.mol) followed by stirring
at room temperature for 2 h were carried out before evaporation of
the solvent. The residue was chromatographed on silica gel (5% to
10% diethyl ether: cyclohexane) to give the title compound (3.39 g,
34%) as a pale yellow oil which was a mixture of diastereomers.
LC/MS: 4.81 min; z/e 605, calcd (M+1) 605. .sup.1H NMR (400 MHz:
CDCl.sub.3): 7.55 (2H), 7.45 (4H), 7.35-6.80 (7H), 4.50 (2H), 3.80
(3H), 3.60 (3H), 2.95 (1H), 2.80 (1H), 2.65 (1H), 1.85 (4H), 1.45
(9H), 0.85 (9H), 0.5 (6H).
Intermediate 7: 1,1-Dimethylethyl
5-(4-biphenylyl)-2-(2-hydroxyethyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)p-
entanoate
[0121] ##STR37##
[0122] A solution of tetra-n-butylammonium fluoride (1.0 M in THF;
6.2 mL, 6.2 mmol) was added dropwise over 15 min to a stirred
solution of 1,1-dimethylethyl
5-(4-biphenylyl)-2-(2-{[(1,1-dimethylethyl)
(dimethyl)silyl]oxy}ethyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)pentanoate
(3.39 g, 5.61 mmol) in tetrahydrofuran (20 mL) at 0.degree. C.
under nitrogen. The reaction was allowed to warm to room
temperature at which stirring was continued for 2 h. The volatiles
were evaporated and the residue partitioned between ethyl acetate
(100 mL) and water (100 mL). The phases were separated and the
aqueous layer was washed with ethyl acetate (3.times.100 mL). The
organic layers were combined, washed with brine (100 mL), dried
(magnesium sulfate) and the solvent evaporated. The residue was
chromatographed on silica gel (50% to 75% diethyl ether:
cyclohexane) to give the title compound (1.6 g, 58%) as a yellow
oil which was a mixture of diastereomers. LC/MS: 3.98 min; z/e 491,
calcd (M+1) 491. .sup.1H NMR (400 MHz: CDCl.sub.3): 7.55 (2H), 7.45
(4H), 7.30 (5H), 6.90 (2H), 4.50 (2H), 3.80 (3H), 3.65 (2H), 2.80
(2H), 2.65 (1H major), 2.05 (1H minor), 1.85 (3H), 1.60-1.35
(11H).
Intermediate 8: 1,1-Dimethylethyl
5-(4-biphenylyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)-2-{2-[(methylsulfon-
yl)oxy]ethyl}pentanoate
[0123] ##STR38##
[0124] Methanesulfonyl chloride (64 .mu.L, 0.83 mmol) was added in
one portion to a stirred solution of 1,1-dimethylethyl
5-(4-biphenylyl)-2-(2-hydroxyethyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)
pentanoate (368 mg, 0.751 mmol) and triethylamine (15.4 mg, 209
.mu.L, 1.52 mmol) in dichloromethane (2 mL) at room temperature
under nitrogen. After stirring at room temperature for 1 h the
crude mixture was partitioned between saturated aqueous citric acid
solution (20 mL) and dichloromethane (20 mL). The phases were
separated and the organic layer was evaporated to give the title
compound (409 mg, 79%) as a yellow oil which was a mixture of
diastereomers. LC/MS: 4.08 min; z/e 586, calcd (M+1) 586. .sup.1H
NMR (400 MHz: CDCl.sub.3): 7.50 (6H), 7.25 (4H), 7.15 (1H), 6.90
(2H), 4.50 (2H), 4.25 (2H), 3.80 (3H), 3.75 (1H), 2.95 (3H),
2.90-2.50 (3H), 2.05 (2H), 1.95-1.65 (2H), 1.55-1.35 (9H).
Intermediate 9: 5-(4-Iodo-phenyl)-3-oxo-pentanoic acid tert-butyl
ester
[0125] ##STR39##
[0126] t-butylacetoacetate (1.5 mL, 9.2 mmol) was added dropwise
over 2 minutes to a stirred suspension of sodium hydride (60%
mineral oil suspension; 400 mg, 10.0 mmol) in tetrahydrofuran at
0.degree. C. under nitrogen. After stirring for 10 minutes n-butyl
lithium in hexane (1.6 M; 6.0 mL, 9.6 mmol) was added then stirring
continued for a further ten minutes. The resulting solution was
treated dropwise with a solution of 4-iodobenzyl bromide (2.97 g,
10.0 mmol) in tetrahydrofuran (4 mL) and then warmed to room
temperature. The reaction was stirred for 40 minutes at room
temperature and then quenched with 6 M HCl (5 mL). The resulting
mixture was extracted with diethyl ether (3.times.50 mL). The
organic phases were combined, washed with brine (50 mL) and dried
(MgSO.sub.4) then the solvent evaporated under reduced pressure.
The residue was purified via flash chromatography on silica gel
(1:20 to 1:10 ethyl acetate/cyclohexane) to give the title compound
(1.88 g, 54%) as a yellow oil. LC/MS: 3.66 min; z/e 375, calcd
(M+1) 375. .sup.1H NMR (400 MHz; CDCl.sub.3): 7.6 (2H), 6.93 (2H),
3.33 (2H), 2.85 (4H), 1.45 (9H).
Intermediate 10: 1,1-Dimethylethyl
2-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-5-(4-iodophenyl)-3-o-
xopentanoate
[0127] ##STR40##
[0128] A solution of 5-(4-iodo-phenyl)-3-oxo-pentanoic acid
tert-butyl ester (10.0 g, 26.7 mmol) in dimethylformamide (25 mL)
was added dropwise over 20 min to a stirred suspension of sodium
hydride (60% mineral oil suspension; 1.12 g, 28.0 mmol) in
dimethylformamide (25 mL) at 0.degree. C. under nitrogen. After
stirring for 20 min (2-bromoethoxy)-t-butyldimethylsilane (7.03 g,
6.31 mL, 29.4 mmol) was added dropwise over 20 min at 0.degree. C.
then the reaction heated to 70.degree. C. for 3.5 h. On cooling to
room temperature the reaction was quenched by careful addition of
water (2 mL) then the volatiles evaporated. The residue was
partitioned between saturated aqueous ammonium chloride solution
(150 mL) and dichloromethane (150 mL) and the phases separated. The
aqueous phase was washed with dichloromethane (3.times.150 mL) then
the organic phases combined, washed with brine (150 mL), dried
(sodium sulfate) and the solvent evaporated. The residue was
chromatographed on silica gel (25% diethyl ether: cyclohexane) to
give the title compound (10.0 g, 70%) as colourless oil which was a
mixture of diastereomers. LC/MS: 4.55 min; z/e 533, calcd (M+1)
533. .sup.1H NMR (400 MHz: CDCl.sub.3): 7.55 (2H), 6.90 (2H), 3.55
(3H), 2.85 (4H), 2.15 (2H minor), 1.95 (2H major), 1.40 (9H), 0.85
(9H), 0.5 (6H).
Intermediate 11: 1,1-Dimethylethyl
2-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-3-hydroxy-5-(4-iodop-
henyl)pentanoate
[0129] ##STR41##
[0130] Sodium borohydride (0.59 g, 15.6 mmol) was added portion
wise to a stirred solution of 1,1-dimethylethyl
2-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-5-(4-iodophenyl)-3-o-
xopentanoate (7.55 g, 14.2 mmol) in methanol (100 mL) at 0.degree.
C. under nitrogen. On completion of addition stirring was continued
for 1.5 h then the reaction was quenched with saturated aqueous
ammonium chloride solution (100 mL). The resulting mixture was
extracted with diethyl ether (3.times.200 mL) then the organic
layers were combined, washed with brine (100 mL), dried (sodium
sulfate) and the solvent evaporated. The residue was
chromatographed on silica gel (25% to 50% diethyl ether:
cyclohexane) to give the title compound (5.14 g, 68%) as a
colourless oil which was a mixture of diastereomers. LC/MS: 4.72
min; z/e 535, calcd (M+1) 535. .sup.1H NMR (400 MHz: CDCl.sub.3):
7.55 (2H), 6.95 (2H), 3.85-3.55 (3H), 3.30 (1H minor), 3.00 (1H
major), 2.80 (1H), 2.65 (1H), 2.55 (1H major), 2.50 (1H minor),
1.95-1.65 (4H), 1.45 (9H), 0.90 (9H), 0.5 (6H).
Intermediate 12: 1,1-Dimethylethyl
2-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-5-(4-iodophenyl)-3-(-
{[4-(methyloxy)phenyl]methyl}oxy)pentanoate
[0131] ##STR42##
[0132] Boron trifluoride etherate (5.0 .mu.L, 39 .mu.mol) was added
to a stirred solution of 1,1-dimethylethyl
2-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-3-hydroxy-5-(4-iodop-
henyl)pentanoate (5.14 g, 9.63 mmol) and 4-methoxybenzyl
2,2,2-trichloroethanimidoate (4.05 g, 14.4 mmol) in tetrahydrofuran
(40 mL) at 0.degree. C. under nitrogen. The reaction was allowed to
warm to room temperature at which stirring was continued for 2 h. A
further portion of boron trifluoride etherate (5.0 .mu.L, 39
.mu.mol) was then added and stirring was continued at room
temperature for a further 2 h. Two further additions of boron
trifluoride etherate (5.0 .mu.L, 39 .mu.mol) followed by stirring
at room temperature for 2 h were carried out before evaporation of
the solvent. The residue was chromatographed on silica gel (0% to
10% diethyl ether: cyclohexane) to give the title compound (4.14 g,
66%) as a yellow oil which was a mixture of diastereomers. LC/MS:
4.78 min; z/e 655, calcd (M+1) 655. .sup.1H NMR (400 MHz:
CDCl.sub.3): 7.55 (2H), 7.25 (2H), 6.90 (2H), 6.80 (2H), 4.55 (1H),
4.35 (1H), 3.80 (3H), 3.65(1H), 3.55 (1H), 2.95 (1H major), 2.80
(1H minor), 2.70 (1H), 2.55 (1H), 1.95-1.60 (4H), 1.45 (9H), 0.85
(9H), 0.5 (6H).
Intermediate 13: 1,1-Dimethylethyl
2-(2-hydroxyethyl)-5-(4-iodophenyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)p-
entanoate
[0133] ##STR43##
[0134] A solution of tetra-n-butylammonium fluoride (1.0 M in THF;
7.0 mL, 7.0 mmol) was added dropwise over 15 min to a stirred
solution of 1,1-dimethylethyl
2-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-5-(4-iodophenyl)-3-(-
{[4-(methyloxy)phenyl]methyl}oxy) pentanoate (4.14 g, 6.33 mmol) in
tetrahydrofuran (25 mL) at 0.degree. C. under nitrogen. The
reaction was allowed to warm to room temperature at which stirring
was continued for 2 h. The volatiles were evaporated and the
residue partitioned between ethyl acetate (100 mL) and water (100
mL). The phases were separated and the aqueous layer was washed
with ethyl acetate (3.times.100 mL). The organic layers were
combined, washed with brine (100 mL), dried (magnesium sulfate) and
the solvent evaporated. The residue was chromatographed on silica
gel (25% to 50% ethyl acteate: cyclohexane) to give the title
compound (2.87 g, 84%) as a yellow oil which was a mixture of
diastereomers. LC/MS: 3.86 min; z/e 541, calcd (M+1) 541. .sup.1H
NMR (400 MHz: CDCl.sub.3): 7.55-7.25 (4H), 6.90-6.75 (4H),
4.55-4.35 (2H), 3.80 (3H), 3.65 (3H), 2.90-2.45 (3H), 1.90-1.60
(4H), 1.35 (9H).
Intermediate 14: 1,1-Dimethylethyl
5-(4-iodophenyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)-2-{2-[(methylsulfon-
yl)oxy]ethyl}pentanoate
[0135] ##STR44##
[0136] Methanesulfonyl chloride (315 .mu.L, 5.91 mmol) was added in
one portion to a stirred solution of 1,1 dimethylethyl
2-(2-hydroxyethyl)-5-(4-iodophenyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)
pentanoate (2.00 g, 3.70 mmol) and triethylamine (1.03 mL, 7.39
mmol) in dichloromethane (10 mL) at room temperature under
nitrogen. After stirring at room temperature for 1 h the crude
mixture was partitioned between saturated aqueous citric acid
solution (40 mL) and dichloromethane (40 mL). The phases were
separated and the organic layer was evaporated to give the title
compound (2.3 g, 100%) as a yellow oil which was a mixture of
diastereomers. LC/MS: 4.00 min; z/e 636, calcd (M+18) 636. .sup.1H
NMR (400 MHz: CDCl.sub.3): 7.60-7.20 (4H), 6.90-6.75 (4H),
4.60-4.20 (5H), 3.80 (3H), 2.95 (3H), 2.90-2.45 (3H), 2.10-1.70
(4H), 1.40 (9H).
Intermediate 15: 1,1-Dimethylethyl
2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-(4-iodophenyl)-3-({-
[4-(methyloxy)phenyl]methyl}oxy)pentanoate
[0137] ##STR45##
[0138] Potassium phthalimide (0.33 g, 2.2 mmol) was added in one
portion to a stirred solution of 1,1-dimethylethyl
5-(4-iodophenyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)-2-{2-[(methylsulfon-
yl)oxy]ethyl}pentanoate (1.15 g, 1.86 mmol) in dimethylformamide (6
mL) at room temperature under nitrogen. The resulting solution was
heated at 80.degree. C. for 1 h 45 min then cooled to room
temperature. The volatiles were evaporated and the residue
partitioned between dichloromethane (50 mL) and water (50 mL). The
layers were separated and the organic phase evaporated to dryness.
The residue was chromatographed on silica gel (50% ethyl acetate:
cyclohexane) to give the title compound (0.26 g, 21%) as a yellow
oil which was a mixture of diastereoisomers. LC/MS: 4.29 min; z/e
687, calcd (M+18) 687. .sup.1H NMR (400 MHz: CDCl.sub.3): 7.85
(2H), 7.70 (2H), 7.55-7.20(4H), 6.90-6.75 (4H), 4.55-4.30 (2H),
3.80 (3H), 3.75 (1H), 3.65 (2H), 2.80-2.45 (3H), 2.10-1.50 (4H),
1.40 (9H).
Intermediate 16: 1,1-Dimethylethyl
5-(4-iodophenyl)-2-[2-(3-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)e-
thyl]-3-({[4-(methyloxy)phenyl]methyl}oxy)pentanoate
[0139] ##STR46##
[0140] 3-Methyl-2,4(1H,3H)-pyrimidinedione (0.28 g, 2.2 mmol) was
added in one portion to a stirred suspension of sodium hydride (60%
suspension in mineral oil; 80 mg, 2.0 mmol) in dimethylformamide (3
mL) at room temperature under nitrogen. The resulting suspension
was stirred for 5 min then a solution of 1,1-dimethylethyl
5-(4-iodophenyl)-3-({[4-(methyloxy)phenyl]methyl}(oxy)-2-{2-[(methylsulfo-
nyl)oxy]ethyl}pentanoate (1.15 g, 1.86 mmol) in dimethylformamide
(3 mL) was added in one portion. The resulting solution was heated
at 80.degree. C. for 1 h 45 min then cooled to room temperature.
The volatiles were evaporated and the residue partitioned between
dichloromethane (50 mL) and water (50 mL). The layers were
separated and the organic phase evaporated to dryness. The residue
was chromatographed on silica gel (10% methanol: dichloromethane)
to give the title compound (0.33 g, 27%) as a yellow oil which was
a mixture of diastereomers. LC/MS: 3.87 min; z/e 649, calcd (M+1)
649. .sup.1H NMR (400 MHz: CDCl.sub.3): 7.55 (2H), 7.25 (2H), 7.10
(1H), 6.90-6.75 (4H), 5.70 (1H), 4.40 (2H), 3.85-3.60 (6H),
3.75-2.45 (3H), 2.00-1.70(4H), 1.40 (9H).
Intermediate 17:
2-[2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-(4-iodoph-
enyl)pentanoic acid
[0141] ##STR47##
[0142] Trifluoroacetic acid (5 mL) was added in one portion to a
stirred solution of 1,1-dimethylethyl
2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-(4-iodophenyl)-3-({-
[4-(methyloxy)phenyl]methyl}oxy)pentanoate (261 mg, 0.390 mmol) in
dichloromethane (5 mL) at room temperature under nitrogen. The
resulting solution was stirred for 45 min then the volatiles
evaporated to give the title compound (192 mg, 100%) as a yellow
solid which was a mixture of diastereomers. LC/MS: 3.32 min; z/e
493, calcd (M+1) 493. .sup.1H NMR (400 MHz: CDCl.sub.3): 7.85 (4H),
7.55 (2H), 6.95 (2H), 4.90 (1H), 3.80-3.50 (3H), 2.70-2.20 (3H),
1.85 (2H), 1.55 (2H).
Intermediate 18:
3-Hydroxy-5-(4-iodophenyl)-2-[2-(3-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyr-
imidinyl)ethyl]pentanoic acid
[0143] ##STR48##
[0144] Prepared by an analogous reaction to intermediate 17. LC/MS:
2.85 min; z/e 473, calcd (M+1) 473.
* * * * *